Shikonin induces ROS-based mitochondria-mediated apoptosis in colon cancer

Abstract

Colon cancer is the third most common malignancy worldwide, and chemotherapy is a widely used strategy in clinical therapy. Chemotherapy-resistant of colon cancer is the main cause of recurrence and progression. Novel drugs with efficacy and safety in treating colon cancer are urgently needed. Shikonin, a naphthoquinone derived from the roots of the herbal plant Lithospermum erythrorhizon, has been determined to be a potent anti-tumor agent. The aim of the present study was to detect the underlying anti-tumor mechanism of shikonin in colon cancer. We found that shikonin suppressed the growth of colon cancer cells in a dose-dependent manner in vitro and in vivo. Shikonin induced mitochondria-mediated apoptosis, which was regulated by Bcl-2 family proteins. Shikonin increased the generation of intracellular ROS, which played an upstream role in shikonin-induced apoptosis. Our data indicated that generation of ROS, down-regulated expression of Bcl-2 and Bcl-xL, depolarization of the mitochondrial membrane potential and activation of the caspase cascade were components of the programmed event of shikonin-induced apoptosis in colon cancer cells. In addition, shikonin presented minimal toxicity to non-neoplastic colon cells and no liver injury in xenograft models, showing safety in the control of colon cancer cell growth in vitro and in vivo. Taken together, our findings suggest that shikonin might serve as a potential novel therapeutic drug in the treatment of human colon cancer.

Antitumor Effect of Shikonin, a PKM2 Inhibitor, in Cholangiocarcinoma Cell Lines

“…Inhibition of CCA cell proliferation and migration by shikonin were rescued by NAC treatment. These results are consistent with previous reports showing that shikonin inhibited cell growth and induced apoptosis of CCA cells via increased ROS(37,38). ROS plays an important role in various diseases, including cancer mediated by different mechanisms and signaling pathways involved in cell proliferation, migration, apoptosis, and senescence.…”

“…ROS plays an important role in various diseases, including cancer mediated by different mechanisms and signaling pathways involved in cell proliferation, migration, apoptosis, and senescence. In cancer suppression, shikonin induced ROS to cytotoxic levels, resulting in inhibition of cell proliferation, migration, invasion and chemoresistance, whereas it induced cell senescence and apoptosis in several cancer types(37)(38)(39).…”

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…There are multiple mechanisms involved in the anticancer effects of shikonin, including ER stress, ROS generation, glutathione (GSH) depletion, mitochondrial membrane potential disruption, p53, superoxide dismutase (SOD) and Bax up-regulation, PARP cleavage, catalase and Bcl-2 down-regulation [591,[612][613][614]. The pro-apoptotic effect of shikonin is also caused by the disruption of intracellular Ca 2+ homeostasis and mitochondrial dysfunction, which involves enhanced Ca 2+ and potassium (K + ) efflux, caspase-3, -8 and -9 activation, and Bcl-2 family protein modulation [615,616]. ERK pathway also plays a role in shikonin-induced anti-cancer effects.…”

Neferine and isoliensinine from Nelumbo nucifera induced reactive oxygen species (ROS)-mediated apoptosis in colorectal cancer HCT-15 cells

“…Contemporary research has shown that the damage of mitochondrial membrane potential leads to mitochondrial mediated apoptosis pathway by release of mitochondrial pro-apoptotic factors (Chen et al, 2018). Several natural products have been reported to induce mitochondrial mediated apoptosis in cancer cells (Liang et al, 2017;Subramanian et al, 2016). Bcl-2 and its homologues inhibit the release of cytochrome c by adhering to the mitochondrial membrane and serve as anti-apoptotic proteins while Bax is known as apoptotic protein which promotes apoptosis.…”